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Hemophilia Gene Therapy Comes of Age

An international group of more than 100 hemophilia researchers met October 21-22, 2016, in Washington, DC, for the National Hemophilia Foundation’s 13th Workshop on Novel Technologies and Gene Transfer for Hemophilia.

What is gene therapy?

The concept of gene therapy is elegant. Both hemophilia A and B are caused by defects in single genes. Therefore, exchanging the defective gene for a functional replacement could potentially reverse the disease and eliminate the need for factor replacement therapy. Even six years ago, gene therapy for hemophilia was a tantalizing promise. Today, it is a reality, though still in early clinical trials.

At the workshop, investigators presented promising results from four ongoing clinical trials of gene therapy for hemophilia B. Hemophilia B was a logical first target because its gene is relatively small and easy to pack into existing viral delivery systems. But four times as many people have hemophilia A. The hurdle to gene therapy for hemophilia A has been that the responsible gene is much larger and harder to deliver to cells.

Now this delivery problem has been solved, as reported by BioMarin Pharmaceutical’s trial of BMN 270. In an ongoing trial, nine volunteers have been treated at three different doses. All participants in the highest-dose group discontinued the use of prophylactic factor VIII therapy over about five months of follow-up. Although liver enzymes rose during treatment, gene expression loss was prevented with short-term steroid administration.

Working around limitations

Treatments directly targeting the genes responsible for hemophilia have made huge strides, but it’s going to be a long time before many patients can be treated with these therapies. In the meantime, researchers are looking for novel ways to work around the limitations of existing treatments, including extending the half-life of treatments and working to better understand why inhibitors develop and finding new ways to prevent them.

The patient point of view

The workshop’s final session featured three patients with severe hemophilia. They gave their opinions on what the past few years of hemophilia treatment advancements—and the promises of the research presented at the workshop—meant to their day-to-day lives.

The first question posed to the panel was whether there are too many products for too few patients. “The answer is no. We’re long overdue for a major realignment in hemophilia care,” responded Brian O’Mahony, CEO of the Irish Haemophilia Society in Dublin. He sees this realignment coming in the next five or so years. “It’s going to be a tremendously exciting time, as we’re going to get all these new generations of treatment,” he added. How quickly these treatments are adopted will hinge on many factors, including cost, O’Mahony said. When recombinant clotting factors first emerged, patients were told they would be plentiful and inexpensive—neither of which turned into a reality, he said.

Insurance companies will certainly do cost-benefit calculations for hemophilia gene therapy, said Randall Curtis, MBA, of the Hemophilia Council of California in Sacramento. Patients will need to tally risk-benefit calculations of their own. These will include whether to try it now, wait for improvements or stick with their current factor replacement therapy if it has served them well. “Risk is a very personal thing,” Curtis said, and how much risk people are willing to accept is heavily influenced by how much the disease affects their life.

“Gene therapy has unknown risks,” said David Page, executive director of the Canadian Hemophilia Society in Montreal. “We have a very short perspective on gene therapy.” Right now, treatment for Page’s hemophilia B gives him adequate factor levels, and he is not willing to jeopardize that. “It would be silly to accept gene therapy when you already have a reasonable therapy with very little risk,” Page said. “But it was great to hear of gene therapy results in the 20% to 40% range for factor IX.” If such levels are shown to be sustained over the years, Page said he might then consider gene therapy.